The present invention relates generally to a therapeutic pharmaceutical composition for the treatment of respiratory disease, including particularly Respiratory Distress Syndrome (RDS) comprised of a synthetic dimer of an N-terminal fragment of Surfactant Protein B (SP-B) that advantageously mimics the functional activity of native human Surfactant Protein B, and to therapeutic methods of administration of such pharmaceutical compositions.
The human lung is composed of a large number of small air sacs, called alveoli, in which gases are exchanged between the blood and the air spaces of the lungs. In healthy individuals, this exchange is mediated by the presence of a protein-containing surfactant complex. Lung surfactant complex is composed primarily of lipid and contains a minor component of various proteins. An absence of adequate levels of this complex results in malfunction of the lung. This syndrome is called Respiratory Distress Syndrome (RDS). Adult RDS is correlated with an absence or dysfunction of the lung surfactant at the alveoli membrane where the gas exchange occurs. The adult disease results from lung insults such as diffuse infections, aspiration of the gastric contents or water, inhalation of irritants and toxins and pulmonary edema arising from such sources as narcotic overdose. The syndrome is also common in premature infants and is associated with immaturity and low birth weight. Of those pre-term infants afflicted, approximately 10% die. Infantile respiratory distress syndrome is the leading cause of death in the first twenty-eight days of life.
Patients with RDS exhibit either abnormal quantities of lung surfactant, an abnormal composition of lung surfactant, or both. Successful treatments focus on replacing surfactant levels and composition to the normal range through surfactant replacement therapy. At the alveolar level, lung surfactant functions prevent excessive accumulation of liquid within the alveolar airspace and stabilize the alveoli and small airways against collapse. A lung surfactant deficiency results in the collapse of the alveoli causing respiratory distress. Surfactant replacement therapy can be used either prophylactically or as rescue treatment for patients with clinical signs of RDS.
The composition of native lung surfactant is lipid (approximately 90%-97%) and various proteins (approximately 10%). The primary lipid type is phospholipid and constitutes 97% of the total lipid. 80% of this phospholipid is phosphatidylcholine (PC) and 10% is phosphatidyglycerol (PG). 70-80% of the phospholipid acyl chains are saturated. The major lipid is dipalmitoylphosphatidylcholine (DPPC). Four surfactant-associated proteins are known to exist: two are glycoproteins, SP-A and SP-D, and two are small hydrophobic proteins, SP-C and SP-B.
Human lung surfactant contains a hydrophobic SP-B peptide, which is usually present as a dimer. The SP-B functions by reducing the surface tension of alveoli to prevent collapse of the lung air sacs, thereby preventing respiratory distress. In the past, surfactant replacement therapies focused on using the lipid components alone. It was later found that the therapy""s performance was greatly improved by the use of the apoprotein in similar proportion to native human surfactant.
Current RDS therapies generally attempt to either utilize natural SP-B or SP-C from other mammals or to synthesize a protein with the functional equivalent of human SP-B. Of the commercially available treatments, the majority utilize natural or modified-natural lung surfactants instead of synthetic surfactants. The natural, animal derived, lung surfactants are harvested from animal lungs either by organic solvent extracts of lung lavage or by organic solvent extracts of minced lungs. The following are commercially available lung surfactants: Curosurf, manufactured by Cheisi Farmeceutici of Italy, is such a natural lung surfactant derived from porcine lung lavage extract. Curosurf contains DPPC in similar proportion to human surfactant and SP-B and SP-C. Another natural lung surfactant, Infasurf, manufactured by Forest Laboratories, is a natural surfactant extract from calf lung lavage. Infasurf is also comprised of phospholipids and SP-B and SP-C. Another commercially available natural lung surfactant is Survanta(copyright), manufactured by Abbott Labs, a chemically modified natural bovine lung extract. The only synthetic lung surfactant therapy commercially available, Exosurf, manufactured by Glaxo Wellcome, is a synthetic protein free surfactant composed of eighty-five percent DPPC, nine- percent hexadecanol and six-percent tyloxapol. Surfactant replacement therapy can be used either prophylactically or as a rescue treatment for patients with clinical signs of RDS.
The present invention includes a pharmaceutical composition of synthetic peptides used to treat respiratory disorders. The composition may also be added to existing treatments to enhance the biological activity of existing pulmonary surfactant dispersions for the treatment of RDS. The invention preferably provides a composition of novel synthetic peptide analogs of SP-B that mimic the active site of native Surfactant Protein B (SP-B) SEQ ID NO: 1. The composition of the invention may be used to supplement naturally derived lung surfactants or to formulate synthetic lung surfactant lipid-peptide dispersions. See Walther, F. J., Hernandez- Juviel, J., Bruni, R., Waring, A. J., xe2x80x9cSpiking Survanta with Synthetic Surfactant Peptides Improves Oxygenation in Surfactant-deficient Rats,xe2x80x9d Am. J. Respir. Crit. Care Med., Vol. 156:855-861, 1997. Unlike protein free formulations, the synthetic peptide of the present invention mimics the active site of the SP-B protein and creates a synthetic analog of these amino acids to augment the properties of the native proteins.
The SP-B analogs of the present invention are based on the known primary sequence of native mammalian SP-B and in a preferred embodiment, human SP-B (SEQ ID NO:2). Specifically, in one preferred embodiment, a covalently linked dimer of the constituent N-terminus SP-B domain (amino acids 1-25), herein referred to as the SP-B1-25 dimer (SEQ ID NO:2), may replace or supplement full length proteins currently used to treat RDS. Because the human peptide is more effective than other natural SP-B derived from animal sources, the creation of a synthetic peptide that mimics human SP-B is more efficacious in the treatment of RDS than natural surfactants derived from animals. Furthermore, the dimeric SP-B1-25 e (SEQ ID NO:2) exhibits advantageous physical and chemical characteristics in analyses that reflect the desired properties of surface tension at the air/liquid interface of the lung. The SP-B1-25 dimer can be formulated in therapeutic compositions for the treatment of respiratory disorders, and can be used in methods designed to treat respiratory disorders when clinically indicated.